Alzheimer's disease (AD) is a progressive, neurodegenerative disorder and is the most common cause of dementia. The disease is characterized by two types of lesions in the brain, abnormal clumps of fibers, called amyloid plaques, and tangled bundles of fibers, called neurofibrillary tangles. Amyloid plaques (also called senile plaques) primarily comprise Aβ peptide. The Aβ peptide is released from the amyloid β protein precursor, APP, by the action of two secretases, and γ (reviewed in Haass, EMBO J. 23:483-488 (2004)). Depending on the γ secretase, Aβ is a 40 or 42 amino acid peptide. While APP is a membrane-spanning protein, Aβ is a soluble peptide. Aβ peptide, however, is highly hydrophobic and readily self-aggregates, forming oligomers. Aggregation of Aβ oligomers results in fiber formation, and the fibers eventually precipitate and develop into the amyloid plaques typical of Alzheimer's and other β amyloidogenic diseases.
Soluble oligomeric forms of Aβ have been postulated to contribute to the onset of AD, and it has been hypothesized that the Aβ peptide causes the pathologic and behavioral manifestations of Alzheimers's disease, including synaptic dysfunction and loss, neurofibrillary tangle formation, neuronal degeneration, and impaired memory (Lambert et al., Proc. Natl. Acad. Sci. USA 95:6448-6453 (1998); Hartley et al., J. Neurosci. 19:8876-8884 (1999); Walsh et al., Science 416:535-539 (2002)). Soluble Aβ levels are increased in individuals with mild cognitive dysfunction in the absence of overt Aβ pathology, and the levels of soluble Aβ levels appear to correlate better with neurofibrillary degeneration and the loss of synaptic markers than do amyloid plaques in AD patients (McLean et al., Ann. Neurol. 46:860-86 (1999); Lue et al., Am. J. Pathol. 155:853-862 (1999); Naslund et al., JAMA 283:1571-1577 (2000)). Similarly, decreases in synaptophysin immunoreactivity and impairments in synaptic transmission in APP transgenic mice precede the onset of microscopic Aβ amyloid pathology (Hsia et al., Proc. Natl. Acad. Sci. USA 96:3228-3233 (1999); Mucke et al., J. Neurosci. 20:4050-4058 (2000)).
A variety of methods designed to inhibit the production or enhance the clearance of Aβ are being developed as potential AD therapies. Indeed, immunization of murine models of Aβ amyloidosis inhibits senile plaque formation, and ameliorates associated cognitive impairments (Schenk, Nature 200:173-177 (1999); Bard et al., Nat. Med. 6:916-919 (2000); Janus et al., Nature 408:979-982 (2000); Morgan et al., Nature 408:982-985 (2000); DeMattos et al., Proc. Natl. Acad. Sci. USA 98:8850-8855 (2001); Hartman et al., Neurosci. 25:6213-6220 (2005)).
Despite the development of meningoencephalitis in 6% of individuals immunized with the Aβ42 peptide during a phase II clinical trial (Nicoll et al., Nat. Med. 9:448-452 (2003); Orgogozo et al., Neurology 61:46-54 (2003)), immunotherapy, especially passive immunization, remains a compelling potential treatment for AD. Interestingly, passive immunization of mouse models of AD-like Aβ plaques has been shown to rapidly reverse learning and memory deficits without affecting Aβ plaque pathology, indicating that neutralization of toxic Aβ species can quickly restore neuronal function in vivo (Dodart et al., Nat. Neurosci. 5:452-457 (2002); Kotilinek et al., J. Neurosci. 22:6331-6335 (2002)).
U.S. Pat. No. 6,913,745 discloses an antibody that selectively binds to an epitope of residues 1-5 of Aβ and its use in a passive immunization method for treating an Alzheimer's disease patient. Gong et al. (PNAS 100:10417-10422 (2003)) disclose polyclonal antibodies raised against oligomers of Aβ1-42. The predominant oligomer detected by the polyclonal antibody is a tetramer. Lambert et al. (J. Neurochem. 79:595-605 (2001)) disclose polyclonal antibodies raised against oligomers of Aβ1-42. The predominant oligomers detected by the polyclonal antibody are trimers and tetramers.
Prior to the present invention, there was an unmet need in the art for an antibody that selectively binds a conformation in toxic Aβ oligomers and does not cross-react with intact APP or C99 for use in passive immunization treatments of β-amyloidogenic diseases. The instant invention meets this need.